Classically closo-carborane anions, particularly HCB11H11− and HCB9H9−, and their derivatives have primarily been used as weakly coordinating anions to isolate reactive intermediates, platforms for ...stoichiometric and catalytic functionalization, counteranions for simple Lewis acid catalysis, and components of materials like liquid crystals. The aim of this article is to educate the reader on the contemporary nonclassical applications of these anions. Specifically, this review will cover new directions in main group catalysis utilized to achieve some of the most challenging catalytic reactions such as C–F, C–H, and C–C functionalizations that are difficult or impossible to realize with transition metals. In addition, the review will cover the utilization of the clusters as dianionic C σ-bound ligands for coordination chemistry, ligand substituents for coordination chemistry and advanced catalyst design, and covalently bound spectator substituents to stabilize radicals. Furthermore, their applications as solution-based and solid-state electrolytes for Li, Na, and Mg batteries will be discussed.
Engineering chimeric antigen receptors (CAR) or T cell receptors (TCR) helps create disease-specific T cells for targeted therapy, but the cost and rigor associated with manufacturing engineered T ...cells ex vivo can be prohibitive, so programing T cells in vivo may be a viable alternative. Here we report an injectable nanocarrier that delivers in vitro-transcribed (IVT) CAR or TCR mRNA for transiently reprograming of circulating T cells to recognize disease-relevant antigens. In mouse models of human leukemia, prostate cancer and hepatitis B-induced hepatocellular carcinoma, repeated infusions of these polymer nanocarriers induce sufficient host T cells expressing tumor-specific CARs or virus-specific TCRs to cause disease regression at levels similar to bolus infusions of ex vivo engineered lymphocytes. Given their ease of manufacturing, distribution and administration, these nanocarriers, and the associated platforms, could become a therapeutic for a wide range of diseases.
Abstract
Aims
To date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the ...prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population.
Methods and results
This prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function reactive hyperaemia index (RHI) was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 75% (95% confidence interval 69–81%) had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P < 0.05 for all associations).
Conclusions
PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.
...immunity against infection might have already begun to wane by December, 2020, because of a general decrease in immune protection against SARS-CoV-2 after a first exposure. ...SARS-CoV-2 lineages ...might evade immunity generated in response to previous infection.15 Three recently detected SARS-CoV-2 lineages (B.1.1.7, B.1.351, and P.1), are unusually divergent and each possesses a unique constellation of mutations of potential biological importance.16–18 Of these, two are circulating in Brazil (B.1.1.7 and P.1) and one (P.1) was detected in Manaus on Jan 12, 2021.16 One case of SARS-CoV-2 reinfection has been associated with the P.1 lineage in Manaus19 that accrued ten unique spike protein mutations, including E484K and N501K.16 Moreover, the newly classified P.2 lineage (sublineage of B.1.128 that independently accrued the spike E484K mutation) has now been detected in several locations in Brazil, including Manaus.20 P.2 variants with the E484K mutation have been detected in two people who have been reinfected with SARS-CoV-2 in Brazil,21,22 and there is in-vitro evidence that the presence of the E484K mutation reduces neutralisation by polyclonal antibodies in convalescent sera.15 Fourth, SARS-CoV-2 lineages circulating in the second wave might have higher inherent transmissibility than pre-existing lineages circulating in Manaus. The protocols and findings of such studies should be coordinated and rapidly shared wherever such variants emerge and spread. Since rapid data sharing is the basis for the development and implementation of actionable disease control measures during public health emergencies, we are openly sharing in real-time monthly curated serosurvey data from blood donors through the Brazil–UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE) Centre GitHub website and will continue to share genetic sequence data and results from Manaus through openly accessible data platforms such as GISAID and Virological.
The Afrotropical mosquito Anopheles gambiae sensu stricto, a major vector of malaria, is currently undergoing speciation into the M and S molecular forms. These forms have diverged in larval ecology ...and reproductive behavior through unknown genetic mechanisms, despite considerable levels of hybridization. Previous genome-wide scans using gene-based microarrays uncovered divergence between M and S that was largely confined to gene-poor pericentromeric regions, prompting a speciation-with-ongoing-gene-flow model that implicated only about 3% of the genome near centromeres in the speciation process. Here, based on the complete M and S genome sequences, we report widespread and heterogeneous genomic divergence inconsistent with appreciable levels of interform gene flow, suggesting a more advanced speciation process and greater challenges to identify genes critical to initiating that process.
Botulinum neurotoxin serotype A (BoNT/A), a potent therapeutic used to treat various disorders, inhibits vesicular neurotransmitter exocytosis by cleaving SNAP25. Development of cell-based potency ...assays (CBPAs) to assess the biological function of BoNT/A have been challenging because of its potency. CBPAs can evaluate the key steps of BoNT action: receptor binding, internalization-translocation, and catalytic activity; and therefore could replace the current mouse bioassay. Primary neurons possess appropriate sensitivity to develop potential replacement assays but those potency assays are difficult to perform and validate. This report describes a CBPA utilizing differentiated human neuroblastoma SiMa cells and a sandwich ELISA that measures BoNT/A-dependent intracellular increase of cleaved SNAP25. Assay sensitivity is similar to the mouse bioassay and measures neurotoxin biological activity in bulk drug substance and BOTOX® product (onabotulinumtoxinA). Validation of a version of this CBPA in a Quality Control laboratory has led to FDA, Health Canada, and European Union approval for potency testing of BOTOX®, BOTOX® Cosmetic, and Vistabel®. Moreover, we also developed and optimized a BoNT/A CBPA screening assay that can be used for the discovery of novel BoNT/A inhibitors to treat human disease.
The interactions that lead to the emergence of superconductivity in iron-based materials remain a subject of debate. It has been suggested that electron-electron correlations enhance electron-phonon ...coupling in iron selenide (FeSe) and related pnictides, but direct experimental verification has been lacking. Here we show that the electron-phonon coupling strength in FeSe can be quantified by combining two time-domain experiments into a “coherent lock-in” measurement in the terahertz regime. X-ray diffraction tracks the light-induced femtosecond coherent lattice motion at a single phonon frequency, and photoemission monitors the subsequent coherent changes in the electronic band structure.Comparison with theory reveals a strong enhancement of the coupling strength in FeSe owing to correlation effects. Given that the electron-phonon coupling affects superconductivity exponentially, this enhancement highlights the importance of the cooperative interplay between electron-electron and electron-phonon interactions.
RAS-pathway mutations are recurrent events in myeloid malignancies. However, there is limited data on the significance of RAS-pathway mutations in patients with myelofibrosis (MF). We analyzed ...next-generation sequencing data of 16 genes, including RAS-pathway genes, from 723 patients with primary and secondary MF across three international centers and evaluated their significance. N/KRAS variants were present in 6% of patients and were typically sub-clonal (median VAF = 20%) relative to other genes variants. RAS variants were associated with advanced MF features including leukocytosis (p = 0.02), high somatic mutation burden (p < 0.01) and the presence of established "molecular high-risk" (MHR) mutations. MF patients with N/KRAS mutations had shorter 3-year overall survival (OS) (34% vs 58%, p < 0.001) and higher incidence of acute myeloid leukemia at 3 years (18% vs 11%, p = 0.03). In a multivariate Cox model, RAS mutations were associated with decreased OS (HR 1.93, p < 0.001). We created a novel score to predict OS incorporating RAS mutations, and it predicted OS across training and validation cohorts. Patients with intermediate risk/high-risk DIPSS with RAS mutations who received ruxolitinib had a nonsignificant longer 2-year OS relative to those who did not receive ruxolitinib. These data demonstrate the importance of identifying RAS mutations in MF patients.
Bevacizumab has been shown to be effective in the treatment of recurrent glioblastoma in combination with chemotherapy compared with historic controls but not in randomized trials.
We conducted a ...retrospective analysis of patients treated for recurrent glioblastoma with bevacizumab vs a control group of patients, comparing progression-free survival (PFS) and overall survival (OS) between the two groups, and performed subgroup analysis based on age and performance status. Expression of vascular endothelial growth factor (VEGF) based on age was examined using DNA microarray analysis. We also evaluated the impact of bevacizumab on quality of life.
We identified 44 patients who received bevacizumab and 79 patients who had not been treated with bevacizumab. There was a significant improvement in PFS and OS in the bevacizumab-treated group. Patients of older age (> or =55 years) and poor performance status (Karnofsky Performance Status < or =80) had significantly better PFS when treated with bevacizumab, and bevacizumab-treated older patients had significantly increased OS. VEGF expression was significantly higher in older glioblastoma patients (aged > or =55 years). Patients treated with bevacizumab also required less dexamethasone use and maintained their functional status longer than the control group.
Bevacizumab in combination with chemotherapy may be a more effective treatment for recurrent glioblastoma and warrants further randomized prospective studies to determine its effect on survival. Bevacizumab also has more effect in those with older age and might reflect biologic differences in glioblastoma in different age groups as seen with the expression of vascular endothelial growth factor.
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